Biomedical subjects
H Rosen
Publications and source records attributed to H Rosen.
Open reduction and internal fixation of the distal humerus: functional outcome in the elderly.
OBJECTIVE: To examine the functional outcome of a cohort of elderly patients after open reduction and internal plate and screw fixation of distal humerus fractures. DESIGN: Retrospective review of a consecutive series of patients older than 60 years of age who underwent plate and screw fixation of a distal humerus fracture. MATERIALS AND METHODS: Eighteen patients, aged 63 to 85 years (average, 71 years), underwent open reduction and internal fixation of a displaced distal humerus fracture using plates and screws. Three were Arbeitsgemeinschaft für Osteosynthesefragen/Association for the Study of Internal Fixation (AO/ASIF) type A, 2 were type B, and 13 were type C fractures. The patients were reviewed at a minimum follow-up of 1 year after surgery. MEASUREMENTS AND MAIN RESULTS: All patients had a good or excellent clinical result using a standardized method of evaluation. General health status, as measured by the SF-36 Health Survey, was comparable to the published norms for U.S. male and female populations of similar age. CONCLUSION: Open reduction and internal fixation of the distal humerus in the elderly can provide good clinical results. Good clinical results, however, do not imply good general health status.
Evaluation of the echinocandin antifungal MK-0991 (L-743,872): efficacies in mouse models of disseminated aspergillosis, candidiasis, and cryptococcosis.
The in vivo activity of the Merck antifungal echinocandin drug candidate MK-0991 (L-743,872) was evaluated in mouse models of disseminated candidiasis, aspergillosis, and cryptococcosis. The echinocandins are potent inhibitors of 1,3-beta-D-glucan synthase. Two models of disseminated candidiasis were used. In a Candida albicans mouse survival model with both DBA/2N and CD-1 mice, estimates of the 50% effective doses (ED50s) of MK-0991 were 0.04 and 0.10 mg/kg of body weight/dose at 21 days after challenge, respectively. In a C. albicans target organ assay (TOA) with DBA/2N mice, MK-0991 at levels of > or =0.09 mg/kg/dose significantly reduced the numbers of C. albicans CFU/g of kidneys compared to the numbers in the kidneys of control mice from 1 to 28 days after challenge. Even when given as a single intraperitoneal dose either 30 min or 24 h after challenge, MK-0991 was effective and significantly reduced the numbers of C. albicans CFU/g of kidney compared to those in the controls. MK-0991 was >300-fold less active when it was administered orally than when it was administered parenterally. MK-0991 was efficacious in mouse TOAs against other C. albicans strains and Candida species including Candida tropicalis, Candida (Torulopsis) glabrata, Candida lusitaniae, Candida parapsilosis, and Candida krusei. MK-0991 was ineffective against disseminated Cryptococcus neoformans infections. In the model of disseminated aspergillosis in mice, MK-0991 at doses of > or =0.02 mg/kg/dose significantly prolonged the survival of DBA/2N mice, with estimates of the ED50 and ED90 of MK-0991 being 0.03 and 0.12 mg/kg/dose, respectively, at 28 days after challenge. MK-0991 is a potent, parenterally administered therapeutic agent against disseminated candidiasis and aspergillosis that warrants further investigation in human clinical trials.
Pharmacokinetics of L-749,345, a long-acting carbapenem antibiotic, in primates.
L-749,345 is a carbapenem antibiotic, currently in phase II clinical trials, which possesses a broad antibacterial spectrum and extended half-life. The time courses of levels of the drugs in plasma and urinary recovery were evaluated for L-749,345, imipenem-cilastatin (IPM), and ceftriaxone (CTX) in male rhesus monkeys (Macaca mulatta) and a chimpanzee (Pan troglodytes). The chimpanzee pharmacokinetics was predictive of human results and indicated a compound that was superior to IPM and approached CTX in its ability to persist in the circulation. Levels of binding to protein, in the range of clinically relevant concentrations in serum, are virtually equivalent for L-749,345 and CTX in humans. Results of a crossover bioassay versus those of a high-pressure liquid chromatography assay of 1-g human samples showed that there were no bioactive metabolites of L-749,345. The extended half-life at elimination phase of L-749,345 allows consideration of single daily dosing. In contrast to results with IPM, the improved stability of L-749,345 with respect to hydrolysis by the renal dehydropeptidase I (0.25 times the rate of IPM) results in urinary recovery sufficient for the drug's use as a single agent.
Redundant contribution of myeloperoxidase-dependent systems to neutrophil-mediated killing of Escherichia coli.
Neutrophil microbicidal activity is a consequence of overlapping antimicrobial systems that vary in prominence according to the conditions of the neutrophil-microbe interaction, the nature of the microbe, and its metabolic state. In this study, normal, myeloperoxidase-deficient, and respiratory burst-deficient (chronic granulomatous disease [CGD]) neutrophils killed Escherichia coli with equivalent, high efficiencies. Killing by CGD and myeloperoxidase-deficient neutrophils was not augmented by supplements, such as exogenous H2O2 and myeloperoxidase, directed at ameliorating their metabolic defects, suggesting that nonoxidative microbicidal systems were sufficient for a full microbicidal effect. Neutrophils with an intact myeloperoxidase antimicrobial system (normal or appropriately supplemented deficient cells) were capable of rapidly suppressing E. coli DNA synthesis, while unsupplemented CGD or myeloperoxidase-deficient cells were far less effective, indicating that the myeloperoxidase system was active in normal neutrophils. The degree of DNA synthesis inhibition by myeloperoxidase-sufficient neutrophils could account, in a cell-free system, for most of the observed microbicidal activity. While the myeloperoxidase system was active and probably bactericidal, it was not rate limiting for microbicidal activity and appears to have been redundant with other microbicidal systems in the cell. Rapid and extensive inhibition of bacterial DNA synthesis appears to be an indicator of myeloperoxidase activity in neutrophils.
Fluorouracil plus racemic leucovorin versus fluorouracil combined with the pure l-isomer of leucovorin for the treatment of advanced colorectal cancer: a randomized phase III study.
PURPOSE: To compare the efficacy and toxicity of fluorouracil (FU) and racemic leucovorin (d,l-LV) versus FU combined with the l-isomer of leucovorin (l-LV) in the treatment of advanced colorectal cancer. PATIENTS AND METHODS: A total of 248 patients with advanced measurable colorectal cancer previously unexposed to chemotherapy were randomly assigned to treatment with either FU (400 mg/m2/d by intravenous [I.V.] infusion for 2 hours) and racemic LV (100 mg/m2/d by I.V. bolus injection) given for 5 consecutive days, or the combination of FU and the pure l-isomer of LV using the same dose schedule. In both treatment arms, courses were administered every 28 days if toxicity allowed for a total of 6 months, unless evidence of tumor progression was documented earlier. RESULTS: There were no significant differences between the FU/racemic LV and the FU/l-LV arm in the overall response rate (25% v 32%), duration of response (7.2 v 8.0 months), median time to progression or death (6.25 v 8.0 months), or median overall survival time (14.5 v 15.0 months). Except for minor myeloid toxic effects associated with FU/l-LV, there was also no significant difference in terms of adverse reactions. Gastrointestinal symptoms, specifically mucasitis and diarrhea, were less frequent and less severe in both treatment arms compared with other trials with FU/racemic LV reported in the literature, which might be because of the prolonged administration of FU used in both arms. CONCLUSION: The combination of FU/l-LV produced response rates, response durations, and survival times similar to those with FU/d,l-LV. Biochemical modulation of FU by either pure l-LV or racemic LV thus appears to result in equivalent clinical efficacy.
Effect of intensive treatment of diabetes of the risk of death or renal failure in NIDDM and IDDM.
OBJECTIVE: To examine the effectiveness and safety of long-term intensive therapy in NIDDM and IDDM. RESEARCH DESIGN AND METHODS: In a private practice setting with a multi-disciplinary team, we compared the rates of total mortality, cardiac-specific mortality, and severe renal failure over 14 years in a cohort of 780 eligible patients, 209 patients with a longer duration of intensive therapy (median duration > 11 years, group I) and 571 patients with shorter duration of intensive therapy (median duration < 1 year, group II). A comorbidity index was used to assess the degree of prognostic risk at baseline. A comprehensive diabetes program was the therapeutic intervention. The endocrinologists and diabetes care team provided primary care, aggressive cardiovascular screening, and risk reduction. Intensive insulin therapy was used in 95.7% of group I IDDM and 66.0% of group I NIDDM patients. RESULTS: The overall median HbA1c for group I was 7.3%. Compared with group II, the overall reduction in cumulative total mortality in group I was 22%. In the cohort with less severe initial comorbidity, the reduction in total mortality was 45%. We found similar reductions in renal failure rates in IDDM and in cardiac mortality in NIDDM patients on intensive insulin therapy. CONCLUSIONS: This comprehensive diabetes program is associated with lowered mortality and morbidity in both IDDM and NIDDM. Intensive insulin therapy in long-term patients with NIDDM does not increase cardiac mortality. Intensive therapy is safe and effective in NIDDM within the context of a comprehensive program.
Salvaging abutment teeth undermined by root surface caries.
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Effective radiochemotherapy with cisplatin and etoposide for the management of patients with locally inoperable and metastatic esophageal carcinoma.
BACKGROUND: The limited therapeutic value of available chemotherapeutic drug combinations in patients with advanced esophageal carcinoma, the documented synergistic activity of etoposide and cisplatin, which might be further enhanced by simultaneous radiotherapy, and promising though only preliminary therapeutic results with this combination regimen have stimulated the present Phase II trial. The specific aim of the study was to determine the efficacy and tolerance of this combined treatment approach in previously untreated patients with either local regional unresectable or metastatic esophageal carcinoma. METHODS: Thirty patients with Stage IIIB or IV squamous cell or adenocarcinoma of the esophagus were entered in this study between October 1992 and November 1994. Chemotherapy was comprised of cisplatin, 30 mg/m2, combined with etoposide, 120 mg/m2, both given intravenously on 4 consecutive days. Treatment courses were repeated every 4 weeks. Radiation therapy (total dose, 5000 centigray) was administered concurrently during the 2nd and 3rd chemotherapy course, during which both drugs were given with a 25% dose reduction. RESULTS: After a median of 4 chemotherapeutic treatment courses (range, 1 to 6 courses), 3 patients had a complete response for 5, 8, and 11.5 months, and 9 patients had a partial response lasting for a median duration of 5.3 months (range, 2.5 to 7.5 months), yielding an overall response rate of 40% (95% confidence interval, 23-59%). The response rates tended to be higher for squamous cell carcinomas (11 of 23; 48%) than for adenocarcinomas (1 of 7), as well as for locoregional disease (7 of 13; 54%) than for patients with disseminated disease (5 of 17; 29%). For the entire study population, median time to progression was 5.4 months (range, 1.5 to 13.5 months), and median survival was 9.2 months (range, 1.5 to 28 months), with 4 patients still alive at the time of this report. Clinically, the most important toxic effect was myelosuppression. Grade 3-4 granulocytopenia occurred in 16 patients (53%), severe thrombocytopenia in 11 (37%), and Grade 3 anemia in 5 (17%). There were four hospitalizations among three patients for the management of fever during neutropenia. Other nonhematologic side effects were generally mild or modest, and most commonly included nausea/emesis (40%), mucositis and/or esophagitis during simultaneous radiotherapy (40%), and alopecia (43%). CONCLUSIONS: Combined radiochemotherapy with cisplatin and etoposide is active against advanced esophageal carcinoma, but can be associated with significant hematotoxicity. Although the therapeutic potential of this regimen appears to be comparable to other, conventional fluorouracil/cisplatin-based chemotherapy, less toxic and more effective regimens need to be identified.
Molecular characterization of immune derived proenkephalin mRNA and the involvement of the adrenergic system in its expression in rat lymphoid cells.
Proenkephalin (PENK), a classically defined opioid gene, was originally thought to be expressed almost exclusively in the mature nervous and neuroendocrine systems. In the last few years, it was demonstrated, however, that significant levels of PENK mRNA and PENK-derived peptides are transiently expressed in cells of the immune system. Very little is known about the molecular mechanisms regulating this transient expression. In order to investigate those mechanisms, we examined the in vivo expression of PENK mRNA in mesenteric lymph nodes after exposing rats to lipopolysaccharide. In the present study we demonstrate that: (i) promoter usage and splicing of PENK mRNA function similarly in mesenteric lymph nodes as in neural cells; (2) PENK expression in mesenteric lymph nodes is modulated by adrenaline via adrenergic receptors; and (3) the adrenergic system participates in the modulation of the LPS induced PENK mRNA expression. These results provide more evidence for the involvement of opioids in neuro-immune interactions.
Peroxynitrite-dependent tyrosine nitration catalyzed by superoxide dismutase, myeloperoxidase, and horseradish peroxidase.
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[Plasminogen activator inhibitor 1 and prognosis in breast carcinoma].
The proteolytic enzyme urokinase-type plasminogen activator (uPA) plays an important role in degrading extracellular matrix. This seems to be an important step in cancer invasion and metastasis. uPA antigen levels correlate significantly with disease recurrence and death in breast cancer. To build up tumour stroma in primary tumours as well as in metastases, inhibition of proteolytic activity is necessary. In this study we investigated the correlation of the Plasminogen Activator Inhibitor 1 (PAI-1), which is the specific inhibitor of uPA and which seems to be important for tumour formation, with prognosis in breast cancer. PAI-1 antigen levels were measured in cytosols of 268 primary breast cancers. In 205 cases we correlated the PAI-1 status (cut-off value: 1 ng/mg) with the clinical outcome. Furthermore we investigated PAI-1 antigen levels in 10 benign breast tumours and 33 metastases. PAI-1 levels were significantly higher in primary carcinomas (median value: 0.62 ng/mg, range: 0 to 30.7) than in benign tumours (median value: 0 ng/mg, range: 0 to 0.1) and metastases showed elevated levels (median value: 1.05 ng/mg, range: 0 to 7.8) in comparison to the primary tumours (Kruskal-Wallis test: p < 0.05). We found that the PAI-1 status correlated significantly with early disease recurrence (Mantel-Test p = 0.0069) and overall survival (Mantel-Test p = 0.0121). After a median follow-up of 32 months (range 2-58), 36% of patients with PAI-1 antigen levels > or = 1 ng/mg (n = 72) showed an early relapse and 24% died, whereas only 19% of patients with PAI-1 antigen levels < 1 ng/mg (n = 133) relapsed and 9% died within the study period. A multivariate analysis revealed that in our study population PAI-1 is not an independent prognostic factor. According to our findings PAI-1 seems to be involved in the formation of extracellular matrix in primary carcinomas and metastases and is related to poor prognosis in breast cancer.
From fedj to social worker: the metamorphosis of a traditional role among Ethiopian immigrants in Israel.
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Aging and medically compromised periodontal prosthodontic patients--salvaging abutment teeth undermined by root surface caries.
Aging and medically compromised patients are retaining their teeth longer. With the prolonged use of medications that produce xerostomia, these patients become more caries susceptible. Root surface caries, which undermines abutment crowns, results in loss of abutments because it is difficult to detect incipient lesions and make appropriate repairs before a significant amount of coronal dentin is lost. With the absence of a significant amount of coronal dentin, routine preparation and impression techniques can result in failure and frustration. For many such patients crown lengthening is the treatment of choice. It provides the restorative dentist convenient access and visibility. However, surgery may be contraindicated because of unfavorable anatomy. It may also be refused by the patient, often upon the advice of a physician. This article provides predictable alternatives for routine preparation and impression techniques. Documentation substantiates the long-term efficacy of these alternatives.
Feminist psychoanalytic theory: American and French reactions to Freud.
Ever since Freud's observations on women and their psychology were published, there have been revisions, expansions, and reactions to his ideas. Most recently, feminist psychoanalytic theorists from the United States and France have been fertile in producing revisions to traditional psychoanalytic theory about women. Reviewing the disjointed psychoanalytic traditions of the two countries provides a context for understanding the different approaches to feminist thinking that each country has produced. American feminist psychoanalytic theorists tend to stage reversals of traditional Freudian theory, while the French feminist psychoanalytic theorists have had to position themselves intellectually and politically with reference to the teachings of Lacan. This paper examines selected contemporary theorists from these two countries--Jean Baker Miller, Nancy Chodorow, and Carol Gilligan from the United States and Julia Kristeva, Luce Irigaray, and Helene Cixous from France--and discusses the difficulties of constructing a theory of sexual difference that avoids the pitfalls of either biological essentialism or its reverse, social constructionism.
Alterations of cell surface antigens induced by placental isoform of ferritin in human carcinoma cell lines.
AIM: the ability of the breast cancer-associated placental acid isoform of ferritin (p43-PLF) to modulate cell surface expression of HLA, CD59 (protectin) and CD66 antigen (adhesion antigen related to CEA) was examined. METHODS: the expression of these antigens in human breast carcinoma cell lines BT-20, T47D and MDA-MB-468 was determined with the aid of flow cytometry and monoclonal antibodies. RESULTS: PLF induced a transient up-regulation followed by a down regulation of cell surface protectin (CD59 antigen) on the cell surface of T47D and to a lesser extent, BT-20 human breast carcinoma cell lines. Furthermore, PLF down-regulated cell surface expression of CEA-related CD66 antigen on both these cell lines. No PLF-induced alterations of protectin, CD66 antigen and HLA class I antigen were found on the MDA-MB-468 breast cancer cell line. CONCLUSIONS: breast cancer-associated p43 induces alterations of the expression of cell surface molecules in breast cancer cells which could have an effect on the modulation of cancer cell adhesive interactions.
A prospective analysis of immunohistochemically determined hormone receptors and nuclear features as predictors of early recurrence in primary breast cancer.
The immunohistochemically determined receptor status, as well as first-generation risk factors (tumor size, lymph node status, histologic grading including subfactors, tumor histology, and biochemically determined receptor status) were prospectively analyzed in 288 cases of primary breast cancer for their impact on recurrence-free survival (RFS) and overall survival (OS) after a median observation period of 41 months. Immunohistochemically (ER-ICA) and biochemically determined estrogen receptors (ER-DCC), as well as tumor size, lymph node status, histologic grading, mitotic rate, and nuclear polymorphism, were of prognostic value for recurrence-free survival and/or overall survival. In multivariate analysis, lymph node status, tumor size, and mitotic rate proved to be independent prognosticators; ER-ICA showed significance in the univariate analysis which dropped, however, when multivariate analysis was applied. The prognostic power of histologic grading in our series seemed to depend mainly on the subfactors which relate to nuclear features.
Both anti-CD11a (LFA-1) and anti-CD11b (MAC-1) therapy delay the onset and diminish the severity of experimental autoimmune encephalomyelitis.
Experimental autoimmune encephalomyelitis (EAE) is a demyelinating disease of the central nervous system (CNS) induced in rodents by activated CD4+ T cells specific for various myelin proteins such as myelin basic protein and proteolipid protein. The disease is characterized by breach of the blood-brain barrier, perivascular infiltration of leukocytes into the CNS, local inflammation and demyelination in the form of plaques. In this study, we evaluated the effect of administration of antibodies to two members of the beta 2 integrin sub-family of adhesion molecules, CD11a and CD11b, on the onset and progression of EAE. CD11a and CD11b are involved in cell-cell interactions leading to T cell and macrophage extravasation to inflammatory sites and T cell activation. Our results show that anti-CD11a antibodies could completely block the induction of EAE and anti-CD11b antibodies significantly delayed the onset and diminished the severity of clinical signs of EAE even when injections were initiated at the first appearance of clinical signs.